Immune reconstitution inflammatory syndrome mimicking relapsing cryptococcal meningitis in a renal transplant recipient.

Immune reconstitution inflammatory syndrome (IRIS) is a rare entity that has been described recently in solid organ transplant (SOT) recipients. IRIS is characterized by an exuberant and dysregulated immune response following treatment of opportunistic infections. We describe here the case of a kidney transplant recipient who developed cryptococcal meningitis that was efficiently treated with antifungal therapy and decreased immunosuppression regimen. Eight months later, a paradoxical worsening of neurological symptoms and neuroradiological findings led to the diagnosis of IRIS. A short course of high-dose steroid therapy allowed complete resolution of neurological symptoms. This report highlights the challenge for physicians to distinguish IRIS from a relapsing cryptococcal infection. Clinical improvement of cryptococcosis-associated IRIS by anti-inflammatory drugs needs to be confirmed among SOT recipients.

Cytomegalovirus risk factors in renal transplantation with modern immunosuppression.

BACKGROUND: Immunosuppressive regimens have lowered the rate of kidney rejection, but with increasing immunodeficiency-related complications. New cytomegalovirus (CMV) prophylaxis also has become available. The impact of these 2 developments on CMV diseases has not been well evaluated. We conducted a randomized trial comparing a drug regimen common in the 1980s, cyclosporin A (CsA) with azathioprine (Aza), with a drug combination used most today, tacrolimus (Tac) with mycophenolate mofetil (MMF), and we analyzed CMV risk factors in kidney transplant patients. METHODS: The 300 patients included in the trial underwent the same universal prophylaxis and preemptive therapy. CMV events and risk factors were prospectively recorded. RESULTS: With preventive and preemptive strategies combined for 3 months, CMV replication was detected in 32.6% and CMV disease in 18.1% of patients. Multivariate analysis on risk factors for CMV disease were CMV donor (D)/recipient (R) matching and first month renal function (risk ratio [95% confidence interval]: 1.02 [1.01; 1.04]; P=0.011), but not the immunosuppressive regimen (P=0.35). The D+/R- combination increased the risk of CMV disease by a factor of 9 (P<0.0001) when compared with D-/R- status, and a factor of 3.5 (P<0.0001) when compared with all CMV-positive recipients. Despite the 50% rate of CMV disease in the D+/R- group, no asymptomatic CMV replication was detected with the preemptive strategy. CONCLUSIONS: With modern immunosuppression, a sequential quadritherapy with Tac/MMF, and a 3-month CMV prevention strategy, the risk for CMV disease remains close to that with CsA/Aza. A CMV-negative recipient transplanted from a CMV-positive donor (D+/R-) remains a major risk factor, calling for better CMV prophylaxis or matching in negative recipients. Preemptive strategy thus appeared inefficient for this high-risk group. Transplant recipients with altered renal function should also be considered at risk.

Kidney transplantation decreases the level and procoagulant activity of circulating microparticles.

Microparticles (MP) are important players in cardiovascular disorders. Renal transplantation significantly improves the survival of hemodialyzed patients, in part because cardiovascular disease (CVD) progression is lessened. We hypothesized that the beneficial effect of renal transplantation on cardiovascular outcome might involve decreased levels of circulating MP. We evaluated the kinetics of MP subpopulations and their procoagulant activity (MP-PCA) in 52 patients before and 3, 6, 9 and 12 months after graft with reference to 50 healthy controls and we evaluated the impact of cardiovascular complications. During the follow-up, the increased levels of MP observed before graft were significantly decreased and reached normal values with different kinetics according to their cellular origin whereas MP-PCA remained significantly higher than in controls. From multivariate analysis, the levels of MP were negatively correlated with renal function. At 12 months, the decrease in MP and MP-PCA was more pronounced in patients without history of CVD than those with. In conclusion, we demonstrated that renal graft is associated with decreased levels of MP levels and MP-PCA, even more pronounced so in patients without history of CVD. Therefore, we suggest that MP lowering could be involved in the vascular dysfunction improvements reported after transplantation.

Contact allergies in haemodialysis patients: a prospective study of 75 patients.

BACKGROUND: Haemodialysis exposes patients to many potentially sensitizing allergens. OBJECTIVES: The primary objective of this study was to evaluate the prevalence of delayed hypersensitivity in a population of haemodialysis patients. Secondary objectives were to identify the possible risk factors for contact sensitization and to propose a series of skin tests adapted to haemodialysis patients. METHODS: A prospective monocentric study was carried out in a nonselected population of haemodialysis patients. For each patient, medical history of atopy and allergic contact dermatitis, ongoing treatments (including topical ones), presence of eczema at the site of vascular access for haemodialysis were recorded. Allergological investigation included delayed hypersensitivity tests (European Environmental and Contact Dermatitis Research Group battery, tests GERDA, additional list and a battery of antiseptics and other dialysis-specific allergens) and latex skin prick test. RESULTS: Seventy-five patients (41 men, 34 women, mean age of 65 years old), with a mean 3.8 years under dialysis, were included. Nineteen patients (25%) had at least one positive skin test and 13 (17%) a positive patch test to at least one allergen relative to dialysis process including eight tests to lidocaine-prilocaine cream and three to povidone-iodine. Tests results seemed clinically relevant since nine patients had localized pruritus at the fistula site and six patients active eczema around it. CONCLUSION: Contact sensitizations are frequent in haemodialysis patients and are linked to vascular access conditioning especially the use of lidocaine-prilocaine cream. Designing a specific test battery could help to diagnose the potential allergens and subsequently to give advice to avoid contact with sensitizing agents.

Human hypertension caused by mutations in WNK kinases.

Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.

Impact of immunosuppressive treatment on endothelial biomarkers after kidney transplantation.

Endothelial dysfunction occurs in hemodialysis and kidney-transplanted patients and can be enhanced by immunosuppressive therapy. Circulating endothelial cells (CEC), endothelial microparticles (EMP) and sVCAM-1 provide information on endothelium activation and damage. We compared the impact of two immunosuppressive regimens (CsA/Aza vs. Tac/MMF) on the kinetics of CEC, EMP and sVCAM-1 levels in 52 patients, both before graft and 3, 6, 9 and 12 months after graft, in reference to 50 healthy controls. CEC, EMP and sVCAM-1 levels were significantly decreased 1 year after transplantation (M12) as compared to pretransplant values. At M12, CEC and sVCAM-1 levels were significantly higher than those of controls whereas EMP reached normal values. Nine months postgraft, lower CEC and normalized EMP levels were found in patients receiving cyclosporine microemulsion/ azathioprine (CsA/Aza) when compared to patients treated with tacrolimus/ mycophenolate mofetil (Tac/MMF). Multivariate analysis evidenced positive correlations between CEC and history of cardiovascular diseases and between EMP and cytomegalovirus infection at M12. In conclusion, our combined analysis of endothelial injury markers confirms the favorable impact of renal transplantation on endothelium, and show that CEC levels discriminate treatment-associated endothelial toxicity. These results enlighten the potential of these noninvasive blood biomarkers in indexing vascular injury and optimize therapeutic options.

Lymphoma-associated hemophagocytic syndrome: a rare cause of severe prerenal acute renal failure.

We report on a 79-year-old woman having hemophagocytosis and capillary hyperpermeability syndrome who presented with anuric prerenal acute renal failure. The patient eventually died of a hypovolemic shock. Post-mortem biopsies evidenced a highly aggressive B cell intravascular lymphoma without amyloidosis. Physicians should be aware of the risk of anuric prerenal acute renal failure in the course of lymphoma-associated hemophagocytic syndrome.

Early IgG glomerulonephritis recurrence in a kidney transplant recipient.

We report a second case of mesangial IgG glomerulonephritis recurrence after kidney allograft transplantation. Mesangial IgG glomerulonephritis is considered a distinct glomerulonephritis. To date, only 1 recurrence after transplantation has been reported. In the present case, recurrence occurred 3 months after transplantation, following an acute rejection episode. Three sequential graft biopsies describe the onset of glomerular lesions.

The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells.

BACKGROUND: Endothelial dysfunction and oxidative stress are matters of concern in patients with chronic renal failure (CRF). Uremic solutes retained in these patients could be involved in these processes. Notably, the protein-bound uremic solute indoxyl sulfate induces endothelial dysfunction in vitro, and has shown pro-oxidant effects. OBJECTIVE: To demonstrate that indoxyl sulfate is a potential mediator of oxidative stress in endothelial cells in vitro. METHODS: Indoxyl sulfate-induced oxidative stress in human umbilical vein endothelial cells (HUVEC) was studied by measuring reactive oxygen specie (ROS) production by cytofluorimetry, by analyzing the involvement of the pro-oxidative enzymes NAD(P)H oxidase, xanthine oxidase, and NO synthase, and by measuring the levels of the non-enzymatic antioxidant glutathione. RESULTS: We showed that indoxyl sulfate induced a significant production of ROS in HUVEC, with or without human serum albumin. We then investigated the role of pro-oxidative enzymes and measured the levels of the antioxidant glutathione. The NAD(P)H oxidase inhibitors, DPI, and apocynin, inhibited ROS production, whereas inhibitors of xanthine oxidase, NO synthase, and mitochondrial ROS had no effect. Interestingly, indoxyl sulfate strongly decreased the levels of glutathione, one of the most active antioxidant systems of the cell. In addition, the ROS production mediated by indoxyl sulfate was inhibited by the antioxidants vitamin C, vitamin E, and NAC. CONCLUSION: The uremic solute indoxyl sulfate enhances ROS production, increases NAD(P)H oxidase activity, and decreases glutathione levels in endothelial cells. Thus, indoxyl sulfate induces oxidative stress by modifying the balance between pro- and antioxidant mechanisms in endothelial cells.

Elevation of circulating endothelial microparticles in patients with chronic renal failure.

BACKGROUND: Chronic renal failure patients are at high risk of cardiovascular events and display endothelial dysfunction, a critical element in the pathogenesis of atherosclerosis. Upon activation, the endothelium sheds microparticles, considered as markers of endothelial dysfunction that also behave as vectors of bioactive molecules. AIM: To measure plasma levels of endothelial microparticles (EMPs) in chronic renal failure patients (CRF), either undialyzed or hemodialyzed (HD), and to investigate the ability of uremic toxins to induce EMP release in vitro. METHODS: Circulating EMPs were numerated by flow cytometry, after staining of platelet-free plasma with phycoerythrin (PE)-conjugated anti-CD144 (CD144+ EMP) or anti-CD146 (CD146+ EMP) monoclonal antibodies. Platelet MP (CD41+ PMP), leukocyte MP (CD45+ leukocyte microparticles (LMP)), and annexin-V+ MPs were also counted. In parallel, MPs were counted in supernatant of human umbilical vein endothelial cells incubated with uremic toxins [oxalate, indoxyl sulfate, p-cresol, and homocysteine (Hcy)], at concentrations found in patients. RESULTS AND CONCLUSIONS: CD144+ EMP and CD146+ EMP levels were significantly higher in CRF and HD patients than in healthy subjects. Furthermore, annexin-V+ MPs were elevated in both groups of uremic patients, and CD41+ PMP and CD45+ LMP were increased in CRF and HD patients, respectively. In vitro, p-cresol and indoxyl sulfate significantly increased both CD146+ and annexin-V+ EMP release. Increased levels of circulating EMP in CRF and HD patients represent a new marker of endothelial dysfunction in uremia. The ability of p-cresol and indoxyl sulfate to increase EMP release in vitro suggests that specific uremic factors may be involved in EMP elevation in patients.

Diagnostic performance of [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography in cyst infection in patients with autosomal dominant polycystic kidney disease.

Cyst infection is a common complication of autosomal dominant polycystic kidney disease (ADPKD). Diagnosis is challenging with standard imaging techniques. We aimed to evaluate the diagnostic performance of [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG PET-CT) for the diagnosis of cyst infections among ADPKD patients, in comparison with computed tomography (CT) and magnetic resonance imaging (MRI). All APKD patients who underwent 18-FDG PET-CT for suspected cyst infection between 2006 and 2013 in a French teaching hospital were included. Diagnosis of cyst infection was retained a posteriori on an index of clinical suspicion. 18-FDG PET-CT findings were was considered to be positive in cases of cyst wall hypermetabolism. CT or MRI findings were were considered to be positive in cases of cyst wall thickening (and enhancement if contrast medium was injected) and infiltration of the adjacent fat. A control group of ADPKD patients with 18-FDG PET-CT performed for other reasons was included. Thirty-two 18-FDG PET-CT scans were performed in 24 ADPKD patients with suspected cyst infection. A diagnosis of cyst infection was retained in 18 of 32 cases: 14 with positive 18-FDG PET-CT findings, and four false negatives. There were no false positives and no hypermetabolism of cyst walls in nine ADPKD control patients. 18-FDG PET-CT had a sensitivity of 77%, a specificity of 100%, and a negative predictive value of 77%. 18-FDG PET-CT allowed a differential diagnosis in three patients. In contrast, CT had a sensitivity of 7% and a negative predictive value of 35% (p <0.001 vs. 18-FDG PET-CT). Only eight MRI scans were performed. The diagnostic performance of 18-FDG PET-CT is superior to that of CT in cyst infections, for comparable radiation doses and with no injection of nephrotoxic contrast medium, in ADPKD patients.

Ascorbic acid-2-0-beta-glucuronide, a new metabolite of vitamin C identified in human urine and uremic plasma.

A new metabolite of ascorbic acid has been isolated by a multi-step chromatographic procedure both from normal human urine and uremic plasma. Nuclear Magnetic Resonance studies, and chemical and enzymic analyses indicated that the compound is a conjugated structure consisting of equimolar ascorbic and beta-D-glucuronic acids. We determined the pKa value of the ascorbic acid moiety of the compound on the basis of variations of ultraviolet absorbances as a function of pH. Results showed that glucuronic acid is coupled to the 2-position of ascorbic acid.

High-resolution NMR studies of transmembrane cation transport in uremic patients.

Cation transport in erythrocytes of some uremic patients is impaired. Most studies have focused on the defect of the erythrocyte Na+/K+ pump in these diseased states. Herein, this cation transport defect was studied by using nuclear magnetic resonance spectroscopy (NMR) which is a non-invasive method permitting study on living erythrocytes. Firstly, we verified that the Na+ transport defect in uremic erythrocytes was not due to non-specific causes such as membrane alteration or a modification of the intracellular metabolism. The proton relaxation data, determined using a paramagnetic doping method, are consistent with a lack of erythrocytic membrane damage in uremic patients. Also, 31P-NMR results showed that in our experimental conditions, uremic and normal erythrocytes exhibit similar variations of ATP level over time. Lastly, the use of anionic paramagnetic shift reagent in 23Na-NMR revealed a defect in the Na+/K+ pump of erythrocytes from uremic patients with high Nain concentration. This defect seems to be due to a reduced number of pump units and to the presence of an endogenous inhibitor in uremic plasma.

Chronic Q fever. Ninety-two cases from France, including 27 cases without endocarditis.

OBJECTIVE: Chronic Q fever is seldom recognized; before 1989, only 234 cases had been reported in the literature. The 92 cases of chronic Q fever collected at the French National Reference Center for Rickettsioses from 1982 through 1990 represent the largest series ever reported. PATIENTS: The patients included in the study were diagnosed between July 31, 1982, and August 1, 1990, at the French National Reference Center for Rickettsioses as having chronic Q fever by the following criteria: presence of antibody against Coxiella burnetii phase I antigen at a titer greater than or equal to 800 for IgG and 50 for IgA by the indirect immunofluorescence test. Epidemiologic, clinical, laboratory, and treatment data were collected from 39 different collaborative hospitals throughout France. MAIN OUTCOME MEASURE: For each serologically selected patient, a computerized questionnaire was utilized to record 188 different items of demographic, epidemiologic, clinical, laboratory, and therapeutic data, which were analyzed. RESULTS: Chronic Q fever occurs more frequently in city dwellers than in rural inhabitants, and exposure to domestic ruminants and raw milk is an important feature. Immunocompromising conditions (20.2%) and underlying heart disease (88.4%) or vascular disease are the most important risk factors to consider in potential cases of chronic Q fever. The mortality in these patients with endocarditis was high (23.5%). The clinical spectrum of 84 patients included 57 cases of endocarditis, three cases of vascular prosthesis infection, three cases of aneurysmal infection, three cases of osteoarthritis, four cases with lung localizations, nine asymptomatic cases, three cases of hepatitis, and two cases with cutaneous forms of the disease. CONCLUSIONS: In patients with unexplained fever, negative blood cultures, and a history of underlying vascular or cardiac disease, Q fever should be considered.

Acute tubular necrosis induced by high level of cyclosporine A in a lung transplant.

We report a case of acute accidental cyclosporine A intoxication in a lung transplant patient. The intoxication led to renal failure due to acute tubular necrosis, which was partially reversible. A review of the literature on the renal consequences of cyclosporine A intoxication is given.

Prevalence of hepatitis G virus infection in kidney transplant recipients.

BACKGROUND: We investigated the prevalence, risk factors, and consequences of hepatitis G virus (HGV) infection in 87 kidney transplant recipients. METHODS: Infection was diagnosed with reverse transcriptase polymerase chain reaction using primers in the NS3 region of the viral genoma. RESULTS: Twenty-four patients (27.5%) were HGV RNA positive (HGV+ group) and 63 patients (72.5%) were HGV RNA negative (HGV- group). No statistically significant differences were found between the two groups for age, sex, transplantation and hemodialysis duration, number of kidney transplantations, serum creatinine, history of transfusions, hepatitis B and C virus infections, and percentage of patients having suffered from acute rejection. Acute and chronic hepatitis were not more prevalent in the HGV+ group than in the HGV- group. CONCLUSIONS: HGV infection is highly prevalent in kidney transplant recipients but does not alter liver or kidney functions. HGV contamination may be linked to nosocomial transmission during long-term hemodialysis.

Cystatin C is not more sensitive than creatinine for detecting early renal impairment in patients with diabetes.

This study evaluated serum cystatin C as a potential new marker of glomerular filtration rate (GFR) in 49 patients who had steady-state diabetes with early renal impairment. We determined the correlation between GFR measured by chromium 51-labeled EDTA and levels of serum cystatin C, serum creatinine, serum beta(2)-microglobulin, endogenous creatinine clearance, and Cockcroft formula. Sensitivity and specificity for the diagnosis of renal failure, defined as a GFR less than either 80 or 60 mL/min/1.73 m(2), were calculated by receiver operating characteristic (ROC) curves for creatinine, cystatin C, and beta(2)-microglobulin. Finally, we compared mean values of these three serum parameters in patients grouped according to GFR using the two definitions of renal failure. Correlation coefficients with GFR were -0.77 for serum creatinine level, -0.65 for serum cystatin C level, -0.71 for serum beta(2)-microglobulin level, +0.56 for endogenous creatinine clearance, and +0.69 for Cockcroft formula (all P < 0.001). With a cutoff value of 60 mL/min/1.73 m(2), areas under the ROC curve were 0.972 for beta(2)-microglobulin, 0.925 for cystatin C, and 0.916 for creatinine levels. With a cutoff value of 80 mL/min/1.73 m(2), these were 0.838 for beta(2)-microglobulin, 0.780 for cystatin C, and 0.905 for creatinine levels (P = not significant between parameters). These results were not altered after the exclusion of patients (n = 8) with a serum creatinine level greater than 1.41 mg/dL. When patients were classified into three groups according to GFR (group 1, >80 mL/min/1.73 m(2); group 2, 60 to 80 mL/min/1.73 m(2); group 3, <60 mL/min/1.73 m(2)), mean values of serum parameters in the three groups were statistically different (P < 0.0001) except between groups 1 and 2 for cystatin C and beta(2)-microglobulin. With patients classified into two groups (GFR > or < 80 mL/min/1.73 m(2)), mean values for each parameter were statistically different (P < 0.001). Sensitivity, specificity, and positive and negative predictive values for serum creatinine and serum cystatin C levels were very close for both definitions of renal failure. Serum cystatin C is not better than serum creatinine or serum beta(2)-microglobulin levels for estimating GFR in patients with steady-state diabetes using ROC curves or other validation tests.

Effect of uremia and hemodialysis on soluble L-selectin and leukocyte surface CD11b and L-selectin.

Leukocyte Mac-1 (CD11b/CD18) and L-selectin (CD62L) are implicated in leukocyte adhesion to endothelial cells. In this study, L-selectin and CD11b expression on leukocytes and soluble L-selectin (sL-selectin) serum levels were investigated in 17 nondialyzed patients with chronic renal failure (CRF), in 28 chronic hemodialysis patients before hemodialysis (basal state), and in 32 healthy subjects. These parameters were also monitored during hemodialysis with cuprophane and cellulose diacetate membranes in a crossover study in five patients. Granulocytes from CRF patients displayed lower expression of L-selectin and higher expression of CD11b than granulocytes from healthy subjects. On the other hand, baseline expression of L-selectin and CD11b on leukocytes from hemodialysis patients did not differ from that of healthy subjects. In CRF and hemodialysis patients, sL-selectin levels were significantly lower than in healthy subjects. During hemodialysis, cuprophane membrane induced an upregulation of granulocyte CD11b, a decrease in granulocyte L-selectin, and an increase in sL-selectin serum levels. Conversely, cellulose diacetate caused only a transient increase in granulocyte CD11b and did not modify granulocyte L-selectin and sL-selectin serum levels. High CD11b and low L-selectin expression on granulocytes in CRF patients suggests an activation state, which was not found in hemodialysis patients at the basal state. The lack of activation in hemodialysis patients could reflect the elimination of a uremic toxin by dialysis or a loss of granulocyte responsiveness because of the repetitive stimulation by hemodialysis treatment. The low serum levels of sL-selectin in CRF and hemodialysis patients also suggest granulocyte dysfunction.

Tubular lesions determine prognosis of IgA nephropathy.

To assess the prognostic value of histological classification for renal outcome, we did a multivariate analysis of 194 patients with immunoglobulin A (IgA) nephropathy between 1985 and 1995. We also evaluated semiquantitative scales of tubular lesions and vessel lesions. At the time of the biopsy, 65 patients (33.5%) had chronic renal failure. At the end of the follow-up, 33 patients (17%) required hemodialysis. The mean age of the patients was 37.8 +/-18.9 years with predominance of men (sex-ratio: 3.12). Patients were followed-up for a mean of 43.2 +/- 37.2 months. Univariate analysis showed that hypertension (P < 10(-4)), nephrotic syndrome (P = 0.01), and crescents (P = 0.02) were significant in predicting renal failure, unlike subendothelial topography of IgA deposits (P = 0.05) and proteinuria (P = 0.05). Hematuria was a protective factor (P = 0.03). Multivariate analysis showed that tubular grade 2 (relative risk [RR], 5.5) and tubular grade 3 (RR = 28.8) were the best factors to predict chronic renal failure. The histological classification of Haas was significant in the univariate analysis, but not in the multivariate analysis. Tubular grading predicted renal outcome better than did the other histological parameters.

Timing of nephrology referral: influence on mortality and morbidity.

To assess the influence of the timing of nephrology referral on the short- and long-term outcome of hemodialysis patients, we retrospectively studied 309 patients who had end-stage renal failure and entered the chronic hemodialysis program in Sainte-Marguerite University Hospital between January 1, 1989, and December 31, 1996. We excluded from the analysis five patients without available data on referral pattern and 34 patients with irreversible acute renal failure. Of the remaining 270 patients, 177 patients (58%) had an early referral (ER) 16 or more weeks before the start of dialysis, and 93 patients (31%) had a late referral (LR) of less than 16 weeks before dialysis. Short-time morbidity (initial emergent dialysis, pulmonary edema, severe hypertension, temporary vascular access placement for first dialysis, prolonged initial hospitalization) was significantly more frequent in LR patients. Long-term evolution (mean follow-up, 26.5 +/- 26 months) did not differ between the two groups. The number of days of hospitalization per patient-year at risk beyond the third month was 21.5 +/- 33.7 days for ER and 21.1 +/- 36 days for LR patients. Survival analysis showed no difference between the two groups: 3-month survival rates were 96% in both groups, 1-year survival rates were 90% in the ER and 89% in the LR group, and 5-year survival rates were 52% in the ER and 56% in the LR group. In a Cox hazards regression model, referral pattern was not associated with a greater risk for death. In conclusion, delayed nephrology referral generated strikingly greater initial morbidity, but long-term outcome of hemodialysis patients was not modified by delayed nephrological care.